tbuckley/cabot-search huggingface dataset:
OTHR-39. Extraneural spreading of a diffuse leptomeningeal glioneuronal tumor in a child: patient-derived models show sensitivity to vinblastin and trametinib
Authors: Julie Messiaen, Annelies Claeys, Aniket Shetty, Lien Spans, Marleen Derweduwe, Anne Uyttebroeck, Bart Depreitere, Isabelle Vanden Bempt, Raf Sciot, Keith Ligon, David Jones, Sandra Jacobs, Frederik De Smet
Journal: Neuro-Oncology (2022)

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare neoplasms of the central nervous system. We describe the generation of patient-derived models from a DLGNT that metastasized to the peritoneal cavity via a ventriculoperitoneal shunt in a child. The original tumor contained a KIAA1549:BRAF fusion with a chromosome 1p deletion and corresponded with methylation subclass DLGNT-MC-2 From a sample of ascitic fluid, metastatic tumoral cells could be extracted and expanded ex vivo into a long-term cell culture model. This patient-derived cell line (PDCL) showed mixed morphological phenotypes and expressed MAP2 and SYP. The KIAA1549:BRAF fusion was preserved and the PDCL still corresponded to the original methylation subclass DLGNT-MC-2. Whole-genome sequencing showed additional mutations potentially contributing to the malignant behavior of the tumor. Cytotoxic assays performed on the PDCL indicated high sensitivity to vinblastine and trametinib (MEK-inhibitor) and intermediate sensitivity to DRD/ClpP-modulators. The PDCL underwent viral transduction to induce GFP-fLux positivity and was intraperitoneally injected into immunocompromised mice. A mouse model could be generated, with the growth of a peritoneal tumor in a localized manner. The cells grown from the mouse tumor were again put into culture and were afterwards subjected to the same treatments as the PDCL. This confirmed a similar profile, with high sensitivity to vinblastin and trametinib and an intermediate sensitivity to the DRD/ClpP-modulators. In conclusion, we were able to generate patient-derived models from a metastatic DLGNT, which recapitulate the molecular characteristics of the original tumor. The models showed high sensitivity to vinblastin and targeted therapy with MEK-inhibition, but further studies are necessary to define the adequate treatment for this kind of tumor.
Representation of women in clinical trials supporting the FDA-approval of contemporary anticancer therapies.
Authors: Melissa A. Babcook, Neha Nidhi, Rebecca R Carter, Janice Bonsu, Vedat Yildiz, Lai Wei, Patrick Ruz, Electra D. Paskett, Daniel Addison
Journal: Journal of Clinical Oncology (2022)

6521 Background: Contemporary anticancer drugs frequently have different efficacy and side effects in men and women. Yet, whether women are well-represented in pivotal trials supporting contemporary anticancer drugs is unknown. The objective of this study was to characterize the representation of women in trials supporting the use of contemporary anticancer drugs. Methods: We retrospectively evaluated all pivotal (phase II and III) trials supporting FDA-approval of anticancer drugs from 1998 to 2018, derived from Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available FDA-drug reviews. Expected population rates were derived from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, and US Census databases. The primary outcome was the report of any gender-specific analysis of efficacy and/or safety, irrespective of treatment-arm. The secondary outcome was the proportional representation of women across trials, evaluated by a participation-to-prevalence ratio (PPR) of 0.85, according to cancer-type. Female representation was also assessed as change across time. Differences in pooled binary endpoint hazard ratios, by the presence or absence of adequate female representation, were also assessed. Results: In total, there were 97,566 participants, enrolled in 189 clinical trials, evaluating 123 anticancer therapies. Gender was reported in 182 (96.3%) clinical trials, of which 43.4% (42,299) were women, compared to 55.6% (55,267) men ( P &lt; 0.01). Overall, women were under-represented in clinical trials of anticancer therapies by a mean of 16.5% compared to the proportional incidence of all cancers in women. Women were the most under-represented in gastric (PPR = 0.821) and liver (PPR = 0.619) cancer trials. Sex-based drug efficacy analysis was only published in 36.8% of trials. Over time, the trend of percentage women recruited into clinical trials increased, but not at a rate comparable to prevalence (-5.0 to -5.5% of prevalence), and the gap in under-representation of women in anticancer therapy clinical trials is widening. Conclusions: Among pivotal clinical trials supporting contemporary FDA-approved cancer drugs, women were frequently under-represented. Additional studies are needed to understand the impact of under-representation on contemporary anticancer therapy outcomes.
MEDB-60. Medulloblastoma with extensive nodularity mimics cerebellar development and differentiates along the granular precursor lineage
Authors: David R Ghasemi, Konstantin Okonechnikov, Stephan Tirier, Anne Rademacher, Jan-Philipp Mallm, Kati Ernst, Karsten Rippe, Andrey Korshunov, Stefan M Pfister, Kristian W Pajtler
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Medulloblastoma with extensive nodularity (MBEN) represents a rare type of cerebellar tumors of infancy comprising two histologically distinct components that differ in cell differentiation and mitotic activity. Whereas some children suffering from MBEN experience disease recurrence, MBEN can also spontaneously differentiate and discontinue to grow. The underlying mechanisms of this variable biological behavior may offer insight into how embryonal tumors develop. METHODS: Fresh frozen and FFPE tumor tissue from nine MBEN-patients was subjected to multi-omics characterization including bulk sequencing, microdissection followed by RNA sequencing, single nucleus RNA-sequencing using the 10X Genomics- and SMART Seq. V2-protocols and spatial transcriptomics via RNAscope. RESULTS: All cases were molecularly classified as Sonic Hedgehog (SHH)-MB, and harbored somatic mutations within the SHH-pathway. After quality control, a total of ~30.000 cells were subjected to downstream analysis. Several non-malignant cell types, such as glial cells, were identified. In accordance with previous studies, we found only sparse immune infiltration. Unsupervised clustering identified cell clusters that differed in differentiation state and represented a continuum from embryonal-like cells with SHH-upregulation over intermediate cell states, to neuronal-like, postmitotic cells. Mapping to a single nucleus sequencing atlas of cerebellar development indicated that tumor cells reflected various stages of normally developing cerebellar granular precursors. Interestingly, one cluster of malignant cells with tumor-specific copy number alterations showed both transcriptomic features of astrocytes and embryonal cells. Using spatial transcriptomics, we were able to correlate different clusters of MBEN cells with distinct histologic MBEN compartments, with astrocyte-like tumor cells being located in the internodular compartment and in close proximity to mitotically active cancer cells. CONCLUSION: MBEN is formed by a continuum of malignant cell differentiation along the granular precursor lineage, with a subset of cells developing into cells that may represent tumor astrocytes. This differentiation process is reflected in the bicompartmental structure of MBEN.
Low-dose apatinib combined with neoadjuvant chemotherapy in the treatment of early-stage triple-negative breast cancer (LANCET): A single-center, single-arm, phase II trial.
Authors: Ciqiu Yang, Junsheng Zhang, Kun Wang
Journal: Journal of Clinical Oncology (2022)

e12613 Background: Anti-angiogenic therapy combined with chemotherapy could improve pathologic complete response for breast cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and standard chemotherapy in patients with triple negative breast cancer (TNBC). Methods: This single-arm, phase II study enrolled patients aged 18-70 years with previously untreated stage IIA-IIIB TNBC. Patients received oral apatinib at a dose of 250 mg once daily and intravenously docetaxel every three weeks for four cycles, followed by epirubicin plus cyclophosphamide every three weeks for four cycles. The primary endpoint was the pathological complete response (pCR) rate in the breast and lymph nodes. Secondary endpoints included objective response rate, event-free survival (EFS), overall survival (OS), and safety. Results: Between August 1, 2018 and March 10, 2021, we screened 34 patients and enrolled 31 patients. At the date of cut-off on December 31, 2021, the median follow-up time was 22.9 months (range: 10.1-41.6 months). The pCR in both breast and lymph nodes were achieved in 17 (54.8%; 95%CI: 36.0–72.7) of 31 patients. Objective responses were achieved in 29 patients (93.5%; 95%CI: 78.6-99.2), and disease control was achieved in 31 patients (100%; 95%CI: 88.8–100.0). The 2-year EFS and 2-year OS were 90.9% and 94.4%, respectively. The five most common treatment-related adverse events were fatigue (51%), hypertension (41%), anorexia (39%), hand-foot syndrome (35%), and diarrhea (32%). Few grade 3 or more adverse events were observed. Conclusions: The combination of apatinib with docetaxel followed by the epirubicin plus cyclophosphamide showed excellent efficacy and manageable toxicities; further randomized controlled phase III trials are warranted. Clinical trial information: NCT03243838.
Projected impact of oncology biosimilar substitution from the perspective of provider risk in value-based oncology payment models.
Authors: Jingyan Yang, Basit Iqbal Chaudhry, Andrew Yue, John M. Kelton, Ahmed Shelbaya, Lisa Tran, Meng Li
Journal: Journal of Clinical Oncology (2022)

e18836 Background: Oncology biosimilars may play an important role in managing risk for providers participating in value-based payment (VBP) models. The impact of biosimilar substitution on risk to providers remains unclear, as prior researchers have adopted a generic budget impact approach. Methods: We estimated the impact of biosimilar substitution on financial risk to providers in oncology VBPs by applying simulation approaches to model the quantitative methodology (e.g. episode framing, pricing, risk adjustment) of Medicare’s Oncology Care Model (OCM). Patient demographic and utilization data to fit the models were drawn from the Medicare Limited Data Set (LDS). Risk was defined as total cost of care (TCOC) relative to target price for an episode per the OCM methodology. Target prices were estimated using the most recently available OCM risk adjustment coefficients (2020). Biosimilars for six oncology agents were examined: bevacizumab, rituximab, trastuzumab, epoetin alfa, filgrastim, and pegfilgrastim (hereafter biosimilar investigation agents – BIAs). Episode TCOC was computed under the assumption of the use of reference BIAs and was then recomputed after biosimilar substitution. The study population consisted of 1620 episodes framed per the OCM methodology using the most recently available LDS data (2019-2020) that had use of a BIA. The impact to provider groups was estimated by computing the change in OCM risk bands (incentive payment earned/ neutral/ payment owed back to Medicare) associated with biosimilar substitution in panels of 100 randomly selected episodes from the study population over 10000 simulation runs. In our base model, we assumed that substitution for antineoplastics would occur only in treatment naïve patients and that substitution for supportive therapies would occur for all eligible patients. Treatment naïve status was assessed by examining longitudinal LDS data from 2016-2020 for beneficiaries from the study population. Results: Biosimilar substitution resulted in a mean reduction in cost relative to target of approximately $1,200 per eligible episode and reduced the proportion of practices that were above benchmark for eligible episodes by 33% and increased the number of practices below target for eligible episodes by 42%. Additional scenario analyses suggested that adoption strategy was a major determinant of potential impact. If assumptions of antineoplastic substitution requiring treatment naïve status were relaxed, costs savings relative to target would go from $1200 per eligible episode to $2700. Conclusions: Biosimilar substitution significantly reduces aggregate provider risk in OCM, representing a significant potential intervention for providers to mitigate risk in oncology VBPs both in terms of absolute costs saved relative to target and reduction in risk band relative to payer projections.
Early Coronary Atherosclerosis in Women With Previous Preeclampsia
Authors: Maria G. Hauge, Peter Damm, Klaus F. Kofoed, Anne S. Ersbøll, Marianne Johansen, Per E. Sigvardsen, Mathias B. Møller, Andreas Fuchs, Jørgen T. Kühl, Børge G. Nordestgaard, Lars V. Køber, Finn Gustafsson, Jesper J. Linde
Journal: Journal of the American College of Cardiology (2022)
Immunotherapeutic effects of recombinant Bacillus Calmette-Guérin containing sic gene in ex vivo and in vivo bladder cancer models
Authors: J.H. Kim, D. Lee, S.H. Ahn, J. Choi, T.-H. Kim, I.H. Chang, B.H. Chi, S.Y. Choi, J.H. Tae, J.H. Shim
Journal: European Urology (2022)
Medications mostly associated with ejaculatory disorders: Assessment of the EudraVigilance (EV) and Food and Drug Administration (FDA) Pharmacovigilance databases entries
Authors: C. De Nunzio, L.M. Rovesti, R. Lombardo, A. Nacchia, A. Cicione, C. Gravina, A. Franco, B. Turchi, G. Guarnotta, O.A. Voglino, E. Mancini, G. Gallo, J. Stira, A. Guercio, V. Baldassarri, S. D'Annunzio, A. Tartarone, F. Di Giacomo, S. Riolo, A. Tubaro
Journal: European Urology (2022)
Identification of CD8+ T cell PRDM1 in high-risk human plaques and its regulatory role in murine lesion development
Authors: SL Maas, H Jin, C Lu, J Nagenborg, M Manca, JMH Karel, R Cavill, O Waring, CJJM Sikkink, BME Mees, MJAP Daemen, E Smirnov, J Sluimer, EPC Van Der Vorst, EAL Biessen
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fritz Thyssen Stiftung T cells have a prominent role in the pathogenesis of atherosclerosis, although their function in atherosclerotic plaques is only partly understood. In this study, we utilize the advantages of high-throughput techniques and data analytic strategies to compare the inherent biological changes of T cells during plaque transition from a stable, non-haemorrhaged (low-risk) to a rupture-prone, haemorrhaged (high-risk) phenotype. We classified 43 human carotid arterial lesions into high- and low-risk plaques based on the presence/absence of intraplaque hemorrhages. RNA from these lesions was isolated and microarray gene expression data was obtained and analyzed by Weighted Gene Co-expression Network Analysis. A strong T cell signalling signature was identified in high- versus low-risk plaques, influencing angiogenesis and interferon-related processes. Bayesian network inference, cell type deconvolution and single-cell RNA sequencing analysis revealed that the T cell-associated gene program was linked to effector-memory cytotoxic, CD8+ T cells. This gene program appeared driven by CD8+ T cell-related transcription factors, including RUNX3, IRF7 and most importantly PRDM1. To validate these findings, we demonstrated in a murine model that T cell PRDM1 plays a key role in plaque formation, as atherosclerotic mice with a T cell specific Prdm1 deficiency developed larger and more advanced atherosclerotic plaques compared to control mice. In conclusion, our study unveils a clear PRDM1-regulated effector-memory cytotoxic CD8+ T cell footprint in plaque development and the shift from low- to high-risk plaques, thereby revealing CD8+ T cells and PRMD1 as potential targets for intervention in adverse T cell responses in human atherosclerotic lesions.
OTHR-13. Effectivity and toxicity of off-label treatment with Trametinib monotherapy or in combination with Dabrafenib in children with relapsed or refractory brain tumor
Authors: S (Selena) Bregonje, E (Evelien) de Vos-Kerkhof, F K (Frederike) Engels, M L C (Marie-Lise) van Veelen, J (Jasper) van der Lugt
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Most pediatric low grade gliomas, and a substantial part of PXAs, have a BRAF alteration/activated MAPK pathway. This group often requires several lines of therapy, which coincides with significant morbidity. There is growing evidence that molecular targeted treatment may be beneficial for this population. Here we report the toxicity and efficacy of patients treated off-trial with either trametinib monotherapy or in combination with dabrafenib. METHODS: We performed a single-center retrospective chart review of all neuro-oncological patients who received trametinib monotherapy or in combination with dabrafenib (compassionate-use) in the Princes Maxima Center between April 1st, 2018 and December 31st, 2021. RESULTS: 22 patients (ages 1-21 years) were included of whom 14 received trametinib monotherapy (BRAF-KIAA fusion, n=10) and eight received trametinib/dabrafenib combination therapy (BRAFV600 mutation, n=8). All patients on trametinib monotherapy (n=14) developed skin problems such as rash (100%), dry skin (86%), paronychia (71%) and eczema (64%). Eight patients (57%) had at least one adverse event (AE) ≥grade 3. Patients on trametinib and dabrafenib showed similar toxicity, although with lower prevalence and no paronychia. One patient (13%) had an AE ≥grade 3. Median treatment time of trametinib was 514 days (IQR 455) and for trametinib and dabrafenib 360 days (IQR 512). Five patients (36%) on trametinib are still on treatment and nine patients (64%) stopped treatment due to e.g. tumor progression or toxicity. All patients on trametinib and dabrafenib are still on treatment. Best overall response of trametinib monotherapy (n=14 evaluated) was observed as partial response (50%), stable disease (33%) and progressive disease (17%). Combination therapy (n=7 evaluated) brought 100% partial response. CONCLUSION: Dermatological toxicities are mostly seen in trametinib monotherapy or in combination with dabrafenib. Despite moderate toxicity patients seem to benefit from treatment. Results suggest that combination therapy has a more favorable toxicity profile than monotherapy.
To be or not to be… treated with initial combination therapy, that is the (PAH) question
Authors: Athénaïs Boucly, Marc Humbert, Olivier Sitbon
Journal: European Respiratory Journal (2022)

<b>Initial <i>versus</i> sequential combination therapy in PAH, that is the question: a robust comparison of these two strategies is needed (initial oral combination <i>versus</i> monotherapy followed by sequential combination therapy when treatment goals are not met)</b>https://bit.ly/35BxQXB
Glycerate from intestinal fructose metabolism induces islet cell damage and glucose intolerance
Authors: Yanru Wu, Chi Wut Wong, Eric N Chiles, Allyson L Mellinger, Hosung Bae, Sunhee Jung, Ted Peterson, Jamie Wang, Marcos Negrete, Qiang Huang, Lihua Wang, Cholsoon Jang, David C Muddiman, Xiaoyang Su, Ian Williamson, Xiling Shen
Journal: Cell Metabolism (2022)
Positive surgical margins after Robot-Assisted Partial Nephrectomy (RAPN): Does it really matter? (MARGINS Study – UroCCR 96)
Authors: A. Morrone, I. Bentellis, J-C. Bernhard, K. Bensalah, C. Champy, F. Bruyere, N. Doumerc, O. Jonathan, F. Audenet, B. Parier, M. Brenier, L. Jean-Alexandre, F.X. Nouhaud, N. Branger, H. Lang, T. Charles, E. Xylinas, T. Waeckel, F. Gomez, R. Boissier, B. Rouget, D. Chevallier, D. Ambrosetti, M. Durand
Journal: European Urology (2022)
LCMC LEADER neoadjuvant screening trial: LCMC4 evaluation of actionable drivers in early-stage lung cancers.
Authors: Boris Sepesi, David Randolph Jones, Bryan F. Meyers, Jamie E. Chaft, Lynette M. Sholl, Yu Shyr, Karen Kelly, Jules Lin, Paul A. Bunn, John D. Minna, Valerie W. Rusch, Ignacio Ivan Wistuba, David J. Kwiatkowski, David Paul Carbone, Lynne D. Berry, Jay M. Lee, Khaled Tolba, Mark G. Kris
Journal: Journal of Clinical Oncology (2022)

TPS8596 Background: Comprehensive genomic profiling (CGP) has transformed the care of patients with advanced non-small cell lung cancer (NSCLC), giving many patients access to precision targeted treatment and immunotherapy with remarkable improvements in outcomes. Studies show that patients with lung cancers with oncogenic drivers are the least likely group to benefit from checkpoint inhibitors and are better served by enrollment in studies of targeted therapies. Early-stage NSCLC is now poised to benefit from these precision approaches with the regulatory approval of the first tyrosine kinase inhibitors and checkpoint inhibitors for the adjuvant treatment of resected NSCLC, each requiring testing for precision biomarkers. Neoadjuvant precision therapy for NSCLC has the potential to further improve treatment outcomes. Methods: The LCMC4 Evaluation of Actionable Drivers in EaRly Stage Lung Cancer (LEADER) Neoadjuvant Screening Trial (NCT04712877) is a collaborative diagnostic study developed by the Lung Cancer Mutation Consortium (LCMC), supported by the Thoracic Surgery Oncology Group and the Lung Cancer Research Foundation. The primary objective is to determine the proportion of patients with stage IA2-III lung cancers who possess actionable oncogenic drivers, defined as 1 of 11 actionable genomic alterations: mutations in EGFR, BRAF V600E , MET exon 14, KRAS G12C, and HER2, rearrangements in ALK, RET, NTRK, and ROS1, and amplification of MET and HER2. The study will also assess the feasibility of CGP to detect actionable oncogenic drivers in patients with suspected early-stage lung cancers scheduled to undergo biopsies to establish the diagnosis of lung cancer. The protocol will enroll 1000 patients with operable stage IA2-III (TNM 8th edition) lung cancer who will undergo CGP utilizing the Foundation Medicine 324 gene assay as well as paired liquid biopsy analysis. Results will enable selection of neoadjuvant therapy and enrollment onto independent therapeutic trials with genomically matched neoadjuvant treatment, standard therapies, or other trials if no driver is detected. The approach will be considered feasible if &gt;35% of non-squamous NSCLCs have 1 of the 11 actionable alterations. Tumor mutational burden and PD-L1 IHC will be assessed. Plasma specimens collected pre- and post neoadjuvant treatment and post-surgery will be used for research to study the ability of circulating tumor DNA to assess neoadjuvant treatment response and minimal residual disease. 26 academic sites in the US plan to enroll patients. Clinical trial information: NCT04712877.